Project Summary (abstract): Despite routine use of sedative-hypnotic and analgesic agents (anesthetics) to prevent or ease suffering during aversive conditions, the effects of these agents on behavior and the neural systems that form memories, respond to threat, and process pain are poorly understood. This project will determine the memory-modulating effects of propofol, dexmedetomidine, and fentanyl in the context of periodic pain stimulation. It is a randomized, placebo- controlled, single-blind, parallel arm fMRI study in healthy adults (under age 40). Subjects will perform a memory encoding task while receiving periodic acute pain stimulation. Explicit and implicit memory will be quantified using response time and physiologic responses, including heart rate and electrodermal activity. Neuroimaging will localize brain activity and connectivity. Psychometric data relevant to pain and anxiety will be used to account for inter-individual differences. The central hypothesis is that, when forming memory during concomitant painful stimulation, three anesthetic agents, with different receptor pharmacology, will have distinct behavioral and physiologic response patterns, which are mediated by different activity within and interactions between the neural systems responsible for memory encoding, threat response, and pain processing. There are three scientific research goals of this patient-oriented career development proposal. The first is to determine how behavioral and physiologic measures of explicit and implicit memory are modulated by pain and the individual effects of the three anesthetics under investigation. The second aim is to determine the brain structures differentially engaged in memory encoding under pain and drug conditions, using task-related functional MRI and functional connectivity analyses. The third aim is to determine brain changes correlated to subject psychometric measures of anxiety, stress, sleep, and pain through multivariate psychophysiological interaction analysis. The scientific framework for this project has a direct application in better understanding the impact of memories formed during sedation with anesthetics while experiencing noxious stimuli. Additionally, further extension of this pharmacologic modulation technique to other cognitive neuroscience paradigms could provide a multidisciplinary framework for basic studies of memory formation, the genesis of dysregulated memories, and the necessary conditions for anesthetic-induced amnesia. In addition to the hands-on research experience of running a trial, achieved through the research aims, this project will advance the applicant into an independent physician scientist in anesthesiology through specific career-development activities. This will be accomplished through a combination of mentoring and evaluation meetings, national scientific/professional meetings, formal didactics, and local seminars/presentations. As part of professional development, coursework in multivariate statistical analysis techniques and cognitive and behavioral neuroscience is planned. The project will be conducted at the University of Pittsburgh, in the School of Medicine, which has outstanding support for clinical and translational research and an established record of developing physician scientists into independent investigators.